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Genetic and chemical activation of TFEB mediates clearance of aggregated ?-synuclein.


ABSTRACT: Aggregation of ?-synuclein (?-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of ?-syn aggregates results from aberrant accumulation of misfolded ?-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In this study, we investigated the role of transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in preventing the accumulation of ?-syn aggregates in human neuroglioma cells. We found that TFEB overexpression reduces the accumulation of aggregated ?-syn by inducing autophagic clearance of ?-syn. Furthermore, we showed that pharmacological activation of TFEB using 2-hydroxypropyl-?-cyclodextrin promotes autophagic clearance of aggregated ?-syn. In summary, our findings demonstrate that TFEB modulates autophagic clearance of ?-syn and suggest that pharmacological activation of TFEB is a promising strategy to enhance the degradation of ?-syn aggregates.

SUBMITTER: Kilpatrick K 

PROVIDER: S-EPMC4366176 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genetic and chemical activation of TFEB mediates clearance of aggregated α-synuclein.

Kilpatrick Kiri K   Zeng Yimeng Y   Hancock Tommy T   Segatori Laura L  

PloS one 20150319 3


Aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of α-syn aggregates results from aberrant accumulation of misfolded α-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In this study, we investigated the role of transcription factor EB (TFEB), a master regula  ...[more]

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